Quinidine usually causes an increase in the serum digoxin concentration (SDC) in otherwise stable patients. Two mechanisms probably cause the increase in SDC. Preliminary studies in both humans and dogs indicate that quinidine reduces renal digoxin clearance and suggest that the magnitude of reduction in digoxin renal clearance is dependent on the serum quinidine concentration. Higher quinidine concentrations than those required to reduce renal clearance often decrease the apparent volume of distribution of digoxin. It is not certain whether or not the increase in SDC is accompanied by an increase in the cardiac effect of digoxin. We have shown that quinidine alters digoxin pharmacokinetics similarly in man and in the dog. Accordingly, we propose to characterize the quinidine-digoxin interaction further and determine its significance using the dog as a model. We plan: (1) to delineate the kinetics of the interaction more precisely, and characterize its dependence on the plasma concentration of quinidine, (2) to determine whether or not quinidine causes changes in tissue concentration of digoxin using tritiated digoxin, (3) to determine whether quinidine increases the cardiac effect of digoxin by using inhibition of myocardial uptake of 86-rubidium to indicate the intensity of digoxin effect at its specific receptor site, (4) to determine whether quinidine interacts with digitoxin, (5) to determine whether structural analogs of quinidine alter digoxin kinetics, and (6) to determine whether the quinidine-digoxin interaction causes digitalis toxicity. The information from these studies will provide vital information on the quinidine-digoxin interaction which will suggest strategies for avoiding toxicity when these two drugs are given together to patients with heart disease.